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Large-scale use of hydroxychloroquine for COVID-19 confirms safety, if not effectiveness

  • Giulio Cavalli
    Affiliations
    Unit of Immunology, Rheumatology, Allergy, and Rare Diseases, IRCCS San Raffaele Scientific Institute; Vita-Salute San Raffaele University, Milan, Italy
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  • Lorenzo Dagna
    Correspondence
    Correspondence to: Prof. Lorenzo Dagna, Unit of Immunology, Rheumatology, Allergy, and Rare Diseases, IRCCS San Raffaele Scientific Institute; Vita-Salute San Raffaele University, via olgettina 60, 20132 Milan, Italy.
    Affiliations
    Unit of Immunology, Rheumatology, Allergy, and Rare Diseases, IRCCS San Raffaele Scientific Institute; Vita-Salute San Raffaele University, Milan, Italy
    Search for articles by this author
Published:October 28, 2020DOI:https://doi.org/10.1016/j.ejim.2020.10.023
      In this issue of the Journal, Di Castelnuovo and colleagues report the findings of the observational multicentre Italian CORIST Study on the use of hydroxychloroquine (HCQ) in hospitalised COVID-19 patients [
      • Castelnuovo A.D.
      • Costanzo S.
      • Antinori A.
      • Berselli N.
      • Blandi L.
      • Bruno R.
      • Cauda R.
      • Guaraldi G.
      • Menicanti L.
      • My I.
      • Parruti G.
      • Patti G.
      • Perlini S.
      • Santilli F.
      • Signorelli C.
      • Spinoni E.
      • Stefanini G.G.
      • Vergori A.
      • Ageno W.
      • Agodi A.
      • Aiello L.
      • Agostoni P.
      • Moghazi S.A.
      • Astuto M.
      • Aucella F.
      • Barbieri G.
      • Bartoloni A.
      • Bonaccio M.
      • Bonfanti P.
      • Cacciatore F.
      • Caiano L.
      • Cannata F.
      • Carrozzi L.
      • Cascio A.
      • Ciccullo A.
      • Cingolani A.
      • Cipollone F.
      • Colomba C.
      • Crosta F.
      • Pra C.D.
      • Danzi G.B.
      • D'Ardes D.
      • d. G. Donati K.
      • Giacomo P.D.
      • Gennaro F.D.
      • Di Tano G.
      • D'Offizi G.
      • Filippini T.
      • Fusco F.M.
      • Gentile I.
      • Gialluisi A.
      • Gini G.
      • Grandone E.
      • Grisafi L.
      • Guarnieri G.
      • Lamonica S.
      • Landi F.
      • Leone A.
      • Maccagni G.
      • Maccarella S.
      • Madaro A.
      • Mapelli M.
      • Maragna R.
      • Marra L.
      • Maresca G.
      • Marotta C.
      • Mastroianni F.
      • Mazzitelli M.
      • Mengozzi A.
      • Menichetti F.
      • Meschiari M.
      • Minutolo F.
      • Montineri A.
      • Mussinelli R.
      • Mussini C.
      • Musso M.
      • Odone A.
      • Olivieri M.
      • Pasi E.
      • Petri F.
      • Pinchera B.
      • Pivato C.A.
      • Poletti V.
      • Ravaglia C.
      • Rinaldi M.
      • Rognoni A.
      • Rossato M.
      • Rossi I.
      • Rossi M.
      • Sabena A.
      • Salinaro F.
      • Sangiovanni V.
      • Sanrocco C.
      • Scorzolini L.
      • Sgariglia R.
      • Simeone P.G.
      • Spinicci M.
      • Trecarichi E.M.
      • Venezia A.
      • Veronesi G.
      • Vettor R.
      • Vianello A.
      • Vinceti M.
      • Vocciante L.
      • De Caterina R.
      • Iacoviello L.
      Use of hydroxychloroquine in hospitalised COVID-19 patients is associated with reduced mortality: Findings from the observational multicentre Italian CORIST study.
      ]. In this large, retrospective cohort of 3,451 COVID-19 inpatients from 33 clinical centers, the use of HCQ was associated with a significant increase in survival. Specifically, the Authors reported an in-hospital death rate of 8.9 per 1,000 person-day for patients receiving HCQ, and of 15.7 for patients not receiving HCQ. Using an inverse probability weighting approach for propensity matching, and adjusting for various possible confounders, the Authors report a 30% reduction in the mortality risk in patients receiving HCQ. While these findings may provide clinical evidence in support of the use of HCQ therapy in patients with COVID-19, the study findings ought to be considered with caution, in light of several limitations, which are inherent to the retrospective, observational design of this study. These include bias by indication (why did some patients receive HCQ in addition to standard management, whereas others did not?), a possible immortal time bias (patients who died before treatment administration tend to be included as controls in retrospective studies), and of the fact that residual confounders typically remain even after stringent propensity matching is applied (not all clinically relevant variables are included in or captured by covariate analyses). However, these inherent limitations should not discourage large, real-world observational studies, which are particularly informative on the safety, rather than the efficacy of medications. In these regards, the study by Di Castelnuovo and colleagues holds clear value.
      Hydroxychloroquine (HCQ) is broadly used for the treatment of autoimmune and rheumatologic conditions such as lupus and rheumatoid arthritis [
      • Touret F.
      • de Lamballerie X.
      Of chloroquine and COVID-19.
      ]. It is orally administered, well tolerated, and safe, as there are no common adverse events typically limiting its use. A feared but utterly rare long-term side effect is retinal deposition leading to progressive visual impairment, whereas theoretical risks of arrhythmic disturbances are clinically negligible (i.e., no cardiac screening is required prior to initiation of HCQ treatment). Before use in autoimmune patients, HCQ was effectively used as an antimalarial agent. Of note, evidence accumulating since the late 1960′s also indicates in vitro antiviral activity [
      • Touret F.
      • de Lamballerie X.
      Of chloroquine and COVID-19.
      ]. Specifically, HCQ interferes with a key step of the infection lifecycle of different viruses, by inhibiting endosomal acidification and viral entry into the host cell. In vitro, this effect prevented infection of target cells by clinical isolates of SARS-CoV-2 [
      • Li G.
      • De Clercq E.
      Therapeutic options for the 2019 novel coronavirus (2019-nCoV).
      ]. Following these and other reports, empirical, large-scale use of HCQ began with the wishful aim of preventing development of COVID-19 or escalation to severe disease states. HCQ was one of many agents used to treat rheumatologic conditions, which were repurposed for use in COVID-19 patients. Other notable examples include biologic cytokine inhibitors such as the interleukin IL-1 blocker anakinra [
      • Cavalli G.
      • De Luca G.
      • Campochiaro C.
      • Della-Torre E.
      • Ripa M.
      • Canetti D.
      • Oltolini C.
      • Castiglioni B.
      • Tassan Din C.
      • Boffini N.
      • Tomelleri A.
      • Farina N.
      • Ruggeri A.
      • Rovere-Querini P.
      • Di Lucca G.
      • Martinenghi S.
      • Scotti R.
      • Tresoldi M.
      • Ciceri F.
      • Landoni G.
      • Zangrillo A.
      • Scarpellini P.
      • Dagna L.
      Interleukin-1 blockade with high-dose anakinra in patients with COVID-19, acute respiratory distress syndrome, and hyperinflammation: a retrospective cohort study.
      ], the IL-6 blockers tocilizumab and sarilumab [
      • Della-Torre E.
      • Campochiaro C.
      • Cavalli G.
      • De Luca G.
      • Napolitano A.
      • La Marca S.
      • Boffini N.
      • Da Prat V.
      • Di Terlizzi G.
      • Lanzillotta M.
      • Rovere Querini P.
      • Ruggeri A.
      • Landoni G.
      • Tresoldi M.
      • Ciceri F.
      • Zangrillo A.
      • De Cobelli F.
      • Dagna L.
      S.-R. S. Group, S.-R. S. G. members
      Interleukin-6 blockade with sarilumab in severe COVID-19 pneumonia with systemic hyperinflammation: an open-label cohort study.
      ,
      • Campochiaro C.
      • Della-Torre E.
      • Cavalli G.
      • De Luca G.
      • Ripa M.
      • Boffini N.
      • Tomelleri A.
      • Baldissera E.
      • Rovere Querini P.
      • Ruggeri A.
      • Monti G.
      • De Cobelli F.
      • Zangrillo A.
      • Tresoldi M.
      • Castagna A.
      • Dagna L.
      Efficacy and safety of tocilizumab in severe COVID-19 patients: a single-centre retrospective cohort study.
      ], and the GM-CSF blocker mavrilimumab [
      • De Luca Giacomo
      • Cavalli Giulio
      • Campochiaro Corrado
      • Della-Torre Emanuel
      • Angelillo Piera
      • Tomelleri Alessandro
      • et al.
      GM-CSF blockade with mavrilimumab in severe COVID-19 pneumonia and systemic hyperinflammation: a single-centre, prospective cohort study.
      ,
      • Bonaventura A
      • Vecchié A
      • Wang TS
      • et al.
      Targeting GM-CSF in COVID-19 Pneumonia: Rationale and Strategies.
      ,
      • Della-Torre E
      • Campochiaro C
      • Cavalli G
      • et al.
      Targeting IL-1, IL-6 or GM-CSF in COVID-19.
      ].
      In general, published studies as well as direct physician experience indicate that HCQ is marginally or not effective for the treatment of COVID-19, regardless of the disease stage and the dose administered [
      • Geleris J
      • Sun Y
      • Platt J
      • et al.
      Observational Study of Hydroxychloroquine in Hospitalized Patients with Covid-19.
      ,
      • Rosenberg ES
      • Dufort EM
      • Udo T
      • et al.
      Association of Treatment With Hydroxychloroquine or Azithromycin With In-Hospital Mortality in Patients With COVID-19 in New York State.
      ,

      Horby P, Mafham M, Linsell L et al. Effect of Hydroxychloroquine in Hospitalized Patients with COVID-19: Preliminary results from a multi-centre, randomized, controlled trial. medRxiv 2020.07.15.20151852. doi: https://doi.org/10.1101/2020.07.15.201518522020.

      ]. However, a controversial, and later retracted publication raised concerns that HCQ might be associated with an increase in the risk of death due to arrhythmia and cardiac events [
      • Mehra MR
      • Desai SS
      • Ruschitzka F
      • Patel AN
      Hydroxychloroquine or chloroquine with or without a macrolide for treatment of COVID-19: a multinational registry analysis.
      ]. This finding, which was in stark contrast with clinical experience with HCQ in immune-rheumatologic conditions, was later debased by a retraction [
      • Mehra MR
      • Ruschitzka F
      • Patel AN
      Retraction-Hydroxychloroquine or chloroquine with or without a macrolide for treatment of COVID-19: a multinational registry analysis.
      ] and refuted by subsequent, separate studies. In these regards, the study by Di Castelnuovo and colleagues is particularly valuable, as included patients had an acute, severe disease, were on concomitant therapies with other drugs, and had pre-existing comorbidities such as ischemic heart disease, cancer and severe chronic kidney disease. Controlled, prospective investigations will determine the efficacy of HCQ in COVID-19. Properly conducted real-world, retrospective investigations can reassure physicians that this old-used medication is generally safe and well tolerated.

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